Unconjugated bilirubin the hydrophobic end-product of heme degradation, is generally held to be little more than a metabolic waste product of heme catabolism. However, the development in mammals of a unique and complex system of synthesis and metabolism of bilirubin supports a potentially important physiologic role for this bile pigment. The broad, long-term objectives of the present application arc to characterize the anti-inflammatory properties of bilirubin and explore the potential therapeutic implications. The experiments outlined in Specific Aim 1 are designed to evaluate the potency and establish the pathways whereby bilirubin suppresses the inflammatory response in vitro, through the use of established rodent models of inflammation. In Specific Aim 2, the mechanism(s) underlying the anti-inflammatory properties of bilirubin will be characterized at the cellular level. Specific Aim 3 will examine whether bilirubin production and catabolism is locally regulated at the site of inflammation, at both the cellular and organismal level. It is anticipated that the results of these studies will provide a more comprehensive understanding of the role that bilirubin plays in the regulation of inflammation and may lay the foundation for potential new therapies for the treatment of inflammatory conditions.